Economic perspective of evaluating fertility treatment in obese and overweight infertile women.

After the conceptualization of idea, the literature search was carried out by using MeSH terms involving the search engines that include Pubmed, Medline, google scholar and open literature. Related research work was then analyzed to find out extent of research carried out on this topic. Relevant papers were screened and added for discussion. A retrospective chart review was conducted between January 2017 and December 2018 at the infertility center of King Fahad Medical City (KFMC) after taking institutional review board approval and according to principles of Helsinki Declaration. The inclusion criteria were all infertile women below the age of 42 who underwent first stimulated IVF cycle. We excluded the male infertility cases, patients with comorbid conditions, those who had freeze-all embryos and cancelled cycles, and those with incomplete data. Within 3 months of the start of the new IVF cycle, BMI was registered and patients were divided into 4 BMI categories; group 1-underweight (30 kg/m 2 ). Data extracted include BMI, age of the female patients, infertility duration, infertility cause, total dosage and duration of gonadotropins utilized for the ovarian stimulation, and direct cost for blood tests and ultrasound scans for monitoring. The findings considered in the study were: day 15 human chronic gonadotr opin (ß-hCG) serum pregnancy hormone test once embryo is transferred, confirming the clinical pregnancy by transvaginal ultrasound 2-4 weeks later to check for fetal heartbeat, transvaginal ultrasound for miscarriage by confirming absent fetal heart. Continuing pregnancy is described as any positive fetal heart pregnancy, visualized on ultrasound at >11 weeks. All women had their details linked electronically with the obstetric outcomes; in case the information was not found, patients were contacted by phone. The initial stimulatory dose of gonadotropins was started depending on day 2 level of follicle-stimulating hormone (FSH), patient’s age, BMI, and antral follicle count (150 IU of gonadotropins was given in women younger than 37 years of age, 225 IU in women aged 37-39, in addition 300 IU for women aged 40 years or older). The patients were monitored using ultrasound reports and serum estradiol levels. A human chorionic gonadotrophin (HCG) trigger was given if minimum of 3 follicles that size greater than 17-18 mm in diameter were visualized by ultrasound. In all females, 2 embryos have been transferred in. All categorical variables such as BMI, parity, miscarriage presented as numbers and percentages. Continuous variable age, duration of infertility and total cost are expressed as Median (interqurtile range). We used non-parametric tests when data was skewed/non-normal data and normality of the data checked by Kolmogorov Smirnov test. Kruskal-Wallis test applied to find out median differences between BMI classifications and clinical characteristics of patients. The exact test of Chi-square/Fisher was applied on the basis of whether the predicted cell frequency was lower than 5 and the significant relation between categorical variables was determined. Data was analyzed on direct costs of IVF in each cohort. For interventions like IVF and ICSI, the costs and clinical outcomes associated with each strategy were compared for different weight groups. The average cost for each cohort of clinical testing was calculated. Regression and correlation analysis was applied to find out significant correlation between total cost (SAR) of IVF and patient’s BMI. A 2-tailed p -value less than 0.05 considered significant for all comparisons. All data was entered and evaluated via the IBM SPSS Statistics for Windows, version XX (IBM Corp., Armonk, N.Y., USA). A bottom-up methodology was used to measure the resource utilization parameters in the reproductive endocrine and infertility medicine department (REIMD); oocyte regeneration, ultrasound scans, blood testing, drug used, embryo transfer and IVF/ICSI. As outlined in REIMD budget, all capital inputs (for example, personnel, facilities, space, and consumables) needed for individual procedures were defined and calculated by consulting with appropriate clinicians and priced using market prices for 2017-2018. The cost of r-FSH (Gonal F) was calculated at a price of 49 Saudi Riyal (SAR) (13$) per 75 units, the cost of human menopausal gonadotropin (Merional) was calculated at a cost 40 SAR (11$) per 75 units, and the baseline cost for IVF/ICSI procedure was calculated at 9000 SAR (2400$) based on market price cost. The cost of biochemical pregnancy; when the pregnancy fails before ultrasound detection of it after a positive pregnancy test; was estimated on the assumption that, on average, each would require one ß-HCG test and ultrasound.

A total of 1157 women underwent IVF/ICSI between January 2017 and December 2018. However, 331 patients were excluded due to; freeze-all embryos (n=209), cancelled cycles (n=106), or cycles that were converted to intrauterine insemination (n=16). A total of 826 patients who fulfilled inclusion criteria were available for analysis; group 1 (n=12) patients (1.5%), group 2 (n=176) patients (21.3%), group 3 (n=338) patients (40.9%) and group 4 (n=300) patients (40.9%) ( Table 1 ). - Descriptive analysis of variables (N=826). HMG: human menopausal gonadotropins, r-FSH: recombinant follicle stimulating hormone Table 2 displays the characteristics of women in each BMI group. There was a trend towards older age in obese women. The median age was 27.5 years in women who were underweight, 31 years in women with normal weight, 33 years in overweight women, and 33 years in obese women ( p <0.001). The duration of infertility was similar across the groups except in the obese group where the duration of infertility was longer, a range of 5 to 10 years and a median of 7 years in the obese group. - Impact and association of body mass index (BMI) with respect to clinical characteristics of the study. FSH: follicle-stimulating hormone, LH: luteinizing hormone, TSH: thyroid stimulating hormone, HMG: human menopausal gonadotropins, IQR: interquartile range IVF-ICSI: in-vitro fertilization/intracytoplasmic sperm injection, r-FSH: recombinant follicle stimulating hormone There were no statistical significant differences in baseline serum FSH, TSH, prolactin and estradiol among the groups; however, there was statistical difference in the level of LH. The median was 7.65 IU/L in women who were underweight, 5.6 IU/L in women with normal weight, 5.1I U/L in women who were overweight, and 6.2 IU/L in those women who were obese ( p =0.03), ( Table 2 ). There were no statistical significant differences for number of days required for stimulation among groups; 10 days for women with underweight and normal weight and 11 days for women with overweight and obese group respectively ( p =0.6). Majority of the patients had IVF-ICSI cycles (n=811, 98.2%) in comparison to IVF (n=15, 1.8%) ( Table 2 ) , and 576 patients (69.7%) had antagonist ovarian stimulation protocol, and 250 (30.3%) had day 21 long ovarian stimulation protocol ( Table 2 ). Of the 826 patients, 347(42%) had a positive pregnancy test and 479 women (58%) had a negative pregnancy test. There was no statistical significant difference in the pregnancy rate among the different BMI groups, pregnancy occurred in 6 women in group 1 (50%), in 63 women in group 2 (35.8%), 144 (42.6%) women occurred in group 3, and 134 (44.7%) women occurred in group 4 ( Table 2 ). No statistical significant differences were seen in miscarriage rates between groups: 18 (10.2%), normal BMI; 45 (13.3%), overweight 47 (15.7%) and among obese women ( p =0.2). No statistical significant differences were seen with regard to frozen embryos among group; 86 (25.4%) in the overweight and 77 (25.7%) in the obese group verses 36 (20.5%) in the normal weight group. There was no statistical significant difference for the LBR among the BMI groups, with the occurrence of LBR in 23 women with normal BMI (13.1%), in 48 (14.2%) women who were overweight, in 48 (16%) in women who were obese ( p =0.7) ( Table 2 ). Besides, the median cost of medications in different groups showed trend increase; however, it was not statistically significant. The cost was 1240 SAR for group 1, 1380 SAR for group 2, 1440 for group 3 and 4 ( p =0.59) ( Table 3 ). The median total cost for IVF/ICSI treatment cycle did not differ across BMI groups; the cost was 10,240 SAR for underweight women, 10,380 SAR for normal weight women, 10,440 SAR for overweight women, and 10,440 SAR for obese women ( p= 0.62) ( Table 3 ). - Comparative analysis of IVF cost and patient’s body mass index. HMG: human menopausal gonadotropins, r-FSH: recombinant follicle stimulating hormone, IQR: interquartile range, IVF-ICSI: in-vitro fertilization/intracytoplasmic sperm injection

The management of infertility has been transformed by the use of assisted reproductive technologies (ART). These developments have a medical, reproductive and economic impact with the cost of a single new IVF in the United States as a proportion of an individual’s annual disposable income was 50%; in the United Kingdom, Scandinavian countries, and Australia, about 20%; and in Japan, 12%. 14 In women with anovulation, where clomiphene citrate is used for ovulation induction (OI) in overweight and obese cohort of women, resulted in lower ovulation and total live birth rates, but if OI is successful, no difference in pregnancy rates is seen in different weight categories. 15 Higher cancellation rates and substantially higher miscarriage rates are also correlated with obesity, resulting in decreased live birth rates. 16 The pregnancy rate and live birth rate decreases due to higher miscarriage rates among obese women such as those found in our study. 17 Lifestyle changes and weight loss programs for obese women have restored menstrual regularity, ovulation and improved the likelihood of conception. 18 A better awareness of the link between the cost, use, and healthy clinical practice of IVF therapy would not only promote equal access to care for patients with subfertility, but also enable children born from IVF get the best possible start in life. 19 Previous studies showed relationship between obesity and ovulatory dysfunction and thus need a higher dose of gonadotrophins; similarly, in our results there was slight increase in gonadotropin requirement in the overweight and obese group, but this did not achieve statistical significance. This is because protocols modify dosage based on the BMI for the IVF cycle. 20 Conflicting results about pregnancy and its outcomes have been found in previous studies, 15 - 19 but we found that the higher the BMI, the higher the likelihood of having a miscarriage. The outcomes per IVF/ICSI may vary because of factors that can affect fertility like age, sperm quality, and comorbid conditions in both partners. In the literature, variable results were obtained for the outcomes in IVF/ICSI for overweight and obese women. 17 , 18 We found no statistically significant differences in IVF/ICSI outcomes among women with different BMI categories. In addition, obesity was associated with pregnancy complications such as high risk of miscarriage, congenital defects, gestational diabetes, hypertensive diseases. It also leads to prolonged labor, fetal macrosomia and increased need for operative delivery, shoulder dystocia, and postpartum hemorrhage. 19 A system within which the effects of fertility therapy and the implications of the subsequent pregnancy can be measured concurrently for infertile women in various groups of body weight needs to be established. It will help reduce the indirect treatment cost for infertility patients by producing a provisional model of working on lifestyle modifications to increase the chances of natural conception. The estimated costs of IVF/ICSI will help us identify cost-effective measures to avoid unnecessary interventions. This study was conducted at a single center therefore, a large sample with multicenter study, can find statistical significance even when the differences or associations are small/weak. Additionally, doctors, researcher and clinicians sometimes misinterpret statistically significant result as being practically or clinically important. But cost significance is not the same as practical significance or importance. Additionally, women in this study were randomly selected on fulfilling the eligibility criteria after initial screening and many women with BMI greater than 35 kg/m 2 were not eligible for treatment, and thus might alter the true number of the obese women in this study. Consequently, our results are not generalizable for women with obesity of BMI more than 35 kg/m 2 . In conclusion, our results suggest that being overweight or obese does not significantly increase the costs of IVF-ICSI. Women could get pregnant if they are overweight or obese but pregnancy might be high risk. Therefore, weight loss measures should be introduced before starting IVF treatment to improve pregnancy outcomes, and reduce obesity linked pregnancy complications.